1. Field of the Invention
The present invention relates to the synthesis of and use of classes of compounds in the treatment of disease, including cancer. A narrow class of analogs of cisplatin has been found to display significantly improved results against a number of types and lines of cancer as compared to closely related analogs.
2. Background of the Art
Cancer is currently the second leading cause of death in the United States, accounting for nearly one-quarter of the deaths. One in two men and one in three women will develop some type of cancer within their lifetime. The American Cancer Society estimated about 1.6 million new cases of cancer in 2012. With such alarming figures, many researchers are working towards the development of new or better treatment for cancer.
Cisplatin (CDDP), approved for clinical treatment by the Food and Drug Administration (FDA) in 1978, belongs to a family of platinum-containing compounds used in the treatment of various types of cancers such as bladder, ovarian, and testicular cancers. While effective as an antitumor agent, its application is limited due to toxic side effects; especially nephrotoxicity. As a consequent of the limitations of cisplatin, numerous analogues have been developed and studied with the goal of finding compounds that could be more effective and possess less toxicity. In 1989, carboplatin was the first cisplatin analogue approved by the FDA for the treatment of lung and ovarian cancer. Oxaliplatin became the third platinum (Pt)-containing compound approved by the FDA in 2002 for the treatment of colorectal cancer. Although carboplatin and oxaliplatin are less toxic than cisplatin, they are either only as effective as or in many cases less effective than cisplatin. Additionally, these analogues also have dose limiting side effects such as myelosuppression. Thus, the search for improved drugs continues.
U.S. Pat. No. 4,177,263 describes various methods for utilizing cisplatin and cisplatin analogs of Pt(II) or Pt(IV) containing various amine and chloro groups to treat tumor cells. It was demonstrated that mouse tumors and leukemia were successfully treated with the described compounds. Although cisplatin was shown to be effective in this patent and is currently used in clinical treatment of various tumors, it has drawbacks such as dose limiting side effects and development of resistance. Additionally, results from our experiments indicate that the novel platinum complexes in this invention are much more potent than cisplatin.
U.S. Pat. No. 4,584,316 describes the synthesis and use of palladium complexes as anti-tumor agents. Of relevance to our invention is the incorporation of the 2,2′-bipyridine ligand in the complex of the formula Pd(II)(cis-2,2′-bipyridine)(NO3)2. This complex gave a percent increased life span (% ILS) of 55-70 when tested on mice; the result is comparable to that of cisplatin which gave a % ILS of 65-80. The compounds were not found to be more effective than cisplatin.
It is known that numerous transition metal complexes, particularly palladium and platinum complexes, have chemotherapeutic activity, as described in U.S. Pat. No. 4,584,316. However, the complexes used at present have a therapeutic index (efficacy/toxicity ratio) which is still too low. Their excessive toxicity limits their use, notably on account of the risk of renal lesions. One way of reducing this major disadvantage is to “isolate” these complexes by incorporation into or association with a vector, permitting a slower diffusion of the active principal. The encapsulation into liposomes of cis-platinum (Freise, J., W. H. Mueller, P. Magerstedt, H. J. Schmoll (1982) Arch. Int. Pharmacodyn., 258, 180) and analogs thereof (Khokhar, A. R., S. Al-Baker, R. Perez-Soler (1988) Anticancer Drug Design 3, 177), reduces the efficacy of these agents, but improves the therapeutic index, prolongs their action, favorably modifies their biodistribution, and even promotes the induction of an antitumor activity against resistant tumors.
Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH3)2Cl2, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et. al. (Nature, 1965, 205, 698; Nature, 1972, 222, 385).
Chemical & Engineering News (Oct. 23, 1995) reported that “Cisplatin was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s. In 1979, it was approved by the Food and Drug Administration for clinical treatment of testicular and ovarian tumors and cancers of the head and neck. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs.”
The Physician's Desk Reference reports that cisplatin (the commercial name is Platinol®) can be used to treat testicular cancer, ovarian cancer, and bladder cancer. Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs.
The compound was shown to be effective for treating leukemia and tumors induced in mice. After so many years, cisplatin is still being widely used because of its efficacy. However, its critical drawback, the toxicity, is still a major concern. Many attempts have been made to either reduce its toxicity or increase its efficacy.
Predominantly, cisplatin binds onto deoxyguanosine of DNA. It also binds onto other deoxynucleosides or nucleosides. Because of the non-selectivity of cisplatin between cancer cells and normal cells, cisplatin has numerous side effects. Besides, cisplatin is effective only to certain kinds of cancers. Therefore, reducing the toxicity of cisplatin and expanding its use in more cancers have been very important issues for all scientists involved in its research.
Many people have attempted to change the ligand on platinum to make new cisplatin analogs in order to reduce the toxicity or improve the efficacy. Examples are made by K. C. Tsou, et al. (J. Clin. Hemat. Oncol. 1977, 7, 322), R. J. Speeder et al. (J. Clin. Hemat. Oncol. 1977, 7, 210), A. Mathew et. al. (Chem. Comm. 1979, 222), D. Rose, et al. (Cancer Treatment Reviews, 1985, 12, 1), and D. Alberts et al. (Cancer Treatment Reviews, 1985, 12, 83).
U.S. Pat. Nos. 5,648,362 and 5,399,694, describe the synthesis and use of, in addition to other complexes, platinum complexes containing 4,4′-substituted-2,2′-bipyridine. The substituents may be —WR1 at the 4 position and —WR2 at the 4′ position or —WR2 at the 4 position with —WR1 at the 4′ position. W can be a methylene, ether, carbonyl, ester, or amide group. R1 contains both a hydrocarbon substituent and a fluoroalkylated substituent; R2 consists of a hydrogen or a hydrocarbon chain. These amphiphilic, fluoroalkylated complexes are to be used when incorporated into liposomes or as emulsions composed of an oily phase, an aqueous phase, and a surfactant. The described invention has drawbacks such as for the synthesis of compounds where W is a methylene; a strong base such as lithium diisopropylamide (LDA) is needed to deprotonate the starting 4,4′-dimethyl-2,2′-bipyridine. LDA is inconvenient as it reacts violently with water; thus, reactions must be performed in specialized glassware under argon or nitrogen. Additionally, if not handled properly, LDA catches fire spontaneously if exposed to air and can release flammable gases which may in turn ignite spontaneously if exposed to water. Another deficiency of the invention is that based on the in vitro results presented most of the synthesized compounds when incorporated into liposomes are less effective than non-encapsulated cisplatin and only one compound had activity close to that of the non-encapsulated cisplatin.
U.S. patent application Ser. No. 11/400,886 describes the synthesis and use of platinum complexes having the formula cis-LPtCl2 (L=4,4′-substituted-2,2′-bipyridine or 4,7-substituted-1,10-phenanthroline) for the treatment of cancer. The substituents are alkyl groups that may include “normal, branched and cyclic alkyl groups, alkyl groups with ether linkages, highly fluorinated alkyl group, highly fluorinated alkyl groups with ether linkages, hydroxyl terminated alkyl groups, hydroxyl-terminated alkyl groups with ether linkages and perfluorinated alkyl groups.” The complexes of this invention are similar to complexes described in U.S. Pat. Nos. 5,648,362 and 5,399,694; however, the complexes do not necessarily have to contain fluorine atoms. Furthermore, manipulation of the compounds is by a suspension or dissolved solution without incorporation into lipids or liposomes. Similar to U.S. Pat. Nos. 5,648,362 and 5,399,694, synthesis of the ligands of U.S. patent application Ser. No. 11/400,886 requires the use of LDA to deprotonate the starting 4,4′-dimethyl-2,2′-bipyridine. As mentioned previously LDA is difficult to work with because of its extreme reactivity with water. Additionally, LDA is a known teratogen.